Rheumatoid arthritis and related conditions are some of the most prevalent diseases throughout the world. In the U.S., over 30 million patients suffer from these debilitating diseases which are characterized by painful and swollen joints due to inflammation in the musculoskeletal tissues of the joints. Over the course of the disease, thickening of the synovial membranes and deformity of the afflicted joints can develop. Although etiology of the disease is unknown, changes in autoimmune functions in genetically susceptible individuals have been often implicated as the primary cause of the disease.
For many decades, non-steroidal anti-inflammatory drugs (NSAIDs) have played an important role in treating these diseases. Among the many NSAIDs which have been introduced, ibuprofen has become one of the most widely used due to its proven efficacy and low cost. Ibuprofen is highly effective for the treatment of many types of inflammatory and arthritic diseases such as rheumatoid arthritis, arthralgia, tendinitis, gout, ankylosing spondylitis, and other related conditions. Due to its potent analgesic and antipyretic activities, ibuprofen is also effective for relief of pain and fever, and is commonly used to relieve muscle ache, neuralgia, dysmenorrhea, headache, and fever.
Oral administration of many NSAIDs, including ibuprofen, can cause serious adverse effects such as gastrointestinal bleeding and ulceration, liver and kidney damages, and central nervous system and cutaneous disturbances, particularly after extended use. Therefore, in an effort to minimize the adverse effects associated with oral administration, non-oral delivery of NSAIDs has been extensively investigated in recent years. Transdermal delivery, in particular, is an attractive option because it avoids the hepatic first-pass metabolism, reduces the side effects associated with oral administration, is associated with higher patient compliance and, in some cases, enhances therapeutic efficacy of the drug.
Although topical administration of certain NSAIDs, such as naproxen, ketoprofen, diclofenac, piroxicam and ibuprofen has been shown to deliver the drug to the local musculoskeletal tissues of joints where arthritic conditions often develop, there is much need to improve efficacy of topically applied NSAIDs. The effectiveness of topical administration of many NSAIDs is limited by the inability of these drugs to permeate the skin. The lack of clinical activity of topical NSAIDs in the treatment of rheumatoid diseases has been attributed to insufficient permeation of the drug through the stratum corneum, the major barrier of the skin towards entry of foreign chemicals. Indeed, among the many factors that potentially affect drug permeation across the skin from topical/transdermal formulations, diffusion of the drug from the vehicle toward the skin surface and subsequent partitioning into the stratum corneum are of particular importance. Some of the approaches that have been used to improve the dermal permeation of drugs are to increase lipophilicity of the drug, to incorporate the drug into lipid vesicles such as liposomes and to employ a permeation enhancer in the formulation. Despite the clear advantages of topical/transdermal therapy as opposed to systemic therapy, the absence of effective transdermal formulations of NSAIDs in the marketplace indicates that efforts directed toward improving the delivery system are extremely important for these drugs.
In most conventional topical formulations of NSAIDs that are commercially available, the active ingredients are simply dissolved, dispersed or otherwise formulated in a suitable pharmaceutical vehicle. The thermodynamic activity of the drug in such formulations is relatively low due to the limited solubility of drugs in the vehicle. For example, in the conventional pharmaceutical creams which are often used as a vehicle for topical delivery, the drug is first dissolved in an oil and then emulsified. For example, in U.S. Pat. No. 5,318,960 (Toppo, issued Jun. 7, 1994) it was disclosed that an ibuprofen-containing composition was formulated by admixing an oil surfactant with an amount of the drug, then adding alcohol and water to obtain an oily dispersion that can be further formulated for improved transdermal delivery. However, the use of a quantity of oil to dissolve the drug dilutes drug concentration in the topical preparation and thus reduces the thermodynamic activity of the active ingredient in the vehicle, the primary driving force for percutaneous absorption. In addition, the limited amount of drug that is dissolved in the oil phase has to diffuse through the surrounding inert oil layer in order to reach the skin surface prior to absorption. Diffusion through the inert oil can be the rate-limiting step in the partitioning of drugs to the skin.
Moreover, some conventional topical formulations containing high amounts of ibuprofen and long chain polymers as solubilizers are unstable, as ibuprofen can react with long chain polymers and has a tendency to crystallize on storage. In an effort to improve the stability of topical pharmaceutical compositions containing ibuprofen, WO 91/04733 (Smith et al.) discloses a eutectic mixture (oily melt) of ibuprofen and menthol, which is formulated into a topical gel containing 3-4%, by weight, of ibuprofen. However, depending on the relative proportion of menthol and ibuprofen, one or both may be present partially in microcrystalline form. In addition, the thermodynamic activity of ibuprofen in the oil phase is relatively low due to the presence of large amounts of menthol (up to 50%).
Stott et al. examined other eutectic systems for transdermal delivery of ibuprofen and found that a binary system consisting of 40:60 ibuprofen:thymol (w/w) showed a eutectic melting point of 32xc2x0 C., which is about the same as the skin temperature used for their permeation studies (J. Controlled Release, 50: 297-308 (1998)). However, any composition of ibuprofen:thymol, other than the 40:60 eutectic mixture, was a two phase system with some of the component remaining as solid. Mixtures containing ibuprofen and L-menthol showed a eutectic melting point of 19xc2x0 C. at 30:70 ibuprofen:L-menthol (w/w), and compositions containing ibuprofen in a ratio of 40:60 were liquid at 32xc2x0 C. Similarly, mixtures containing ibuprofen and LD-menthol showed a eutectic melting point of 13xc2x0 C. at 25:75 ibuprofen:LD-menthol (w/w). Thus, the only binary mixtures potentially suitable for topical formulations of ibuprofen as an oily melt were those having very narrow compositional ranges and containing relatively low amounts of ibuprofen. The permeability through human epidermal membranes was enhanced when ibuprofen was delivered by way of a eutectic formulation. The largest flux increase at 32xc2x0 C. was obtained from ibuprofen:thymol mixtures at the weight ratios that included the eutectic compositions (35:65 and 40:60, w/w). Notably, increased flux was not observed for saturated ibuprofen:thymol mixtures above 40:60, w/w. On the other hand, maximum fluxes for the ibuprofen:menthol mixtures were observed for mixtures containing ibuprofen in concentrations high enough (e.g., 50:50 ibuprofen:LD-menthol, w/w) to contain some solid at 32xc2x0 C., analogous to a saturated solution. The authors warn, however, that if the amount of ibuprofen is further increased, the system becomes xe2x80x9ctoo solidxe2x80x9d and difficult to apply to the membrane.
Chemically, ibuprofen is a-methyl-4-(2-methylpropyl) benzene-acetic acid. It has one chiral center, thus there are two enantiomers, S(+)-ibuprofen and R(xe2x88x92)-ibuprofen, also known as S-ibuprofen and R-ibuprofen. The racemic form consisting of equal amounts of S(+)-ibuprofen and R(xe2x88x92)-ibuprofen is exclusively used in presently available commercial preparations. Racemic ibuprofen a high melting point (about 78xc2x0 C.), while both stereoisomers of ibuprofen, S(+)-ibuprofen and R(xe2x88x92)-ibuprofen, melt at 44xc2x0 C. All these forms are poorly soluble in water. And, although ibuprofen is a lipophilic drug, it does not permeate the skin well. Notably, the S(+) form alone appears to be responsible for the anti-inflammatory activity, not the R(xe2x88x92) form (S. Adams et al., Curr. Med. Res. Opin., 3, 552 (1975); S. Adams et al., J. Pharm. Pharmacol., 28, 256-257 (1976)). Accordingly, some investigators have described anti-inflammatory compositions containing substantially pure S(+)-ibuprofen.
Japanese patent application JP 06199701 describes anti-inflammatory analgesic compositions comprising ibuprofen (up to 1%, by weight), preferentially in the S(+)-form, and a high concentration of polyhydric alcohol that purportedly increases absorption of the drug from the skin. Due to the presence of a large amount of alcohols in the formulations, the majority of NSAIDs will be dissolved in the vehicle. U.S. Pat. No. 5,093,133 (Wisniewski et al., Mar. 3, 1992) describes topical compositions containing somewhat higher concentrations of S(+)-ibuprofen, but these compositions also contain high concentrations of alcohols, as much as 50%., which solubilize ibuprofen without forming a large oil phase.
Since pharmacological actions depend on drug concentrations at pathological sites, it is readily apparent that effective transdernal delivery of clinically significant amounts of NSAIDs, especially ibuprofen, to a target site remains an important challenge for pharmaceutical scientists.
A novel composition is provided that can be readily formulated into a topical anti-inflammatory preparation. Preferred embodiments of the anti-inflammatory preparation of the invention are characterized by enhanced transdermal absorption. The composition has two liquid phases: an aqueous phase and an oil phase, wherein the oil phase has a relatively high concentration of a nonsteroidal anti-inflammatory drug (NSAID). An aqueous phase is a phase that comprises water. Preferably, both the aqueous phase and the oil phase are homogeneous. A xe2x80x9chomogenousxe2x80x9d aqueous phase or oil phase is a liquid phase in which none of the components is present in a solid state. The aqueous and oil phases of the composition of the invention are preferably homogenous phases at about 37xc2x0 C.; more preferably, they are homogenous phases at about 25 xc2x0 C. It should nonetheless be understood that the invention also encompasses two phase liquid compositions that contain nonhomogenous aqueous and/or oil phases; that is, the presence of some crystalline solids in the aqueous phase or the oil phase, or both, is not necessarily excluded.
The concentration of the anti-inflammatory agent in the oil phase of the composition is preferably at least about 40%, by weight, of the weight of the oil phase; more preferably it is at least about 50%, by weight, of the weight of the oil phase; even more preferably it is at least about 60%, by weight, of the weight of the oil phase; most preferably it is at least about 70%, by weight, of the weight of the oil phase of the composition.
A preferred two phase liquid composition of the invention contains:
(a) at least one nonsteroidal anti-inflammatory drug (NSAID), preferably at least about 1% of the total composition, by weight, more preferably at least about 3% of the total composition, by weight, most preferably at least about 5% of the total composition, by weight; and preferably less than about 30% of the total composition, by weight, more preferably less than about 20% of the total composition, by weight, most preferably less than about 10% of the total composition, by weight;
(b) at least one first melting point depressing agent, preferably at least about 1% of the total composition, by weight, more preferably at least about 5% of the total composition, by weight, most preferably at least about 10% of the total composition, by weight; and preferably less than about 40% of the total composition, by weight, more preferably less than about 30% of the total composition, by weight, most preferably less than about 2 0% of the total composition, by weight; and
(c) water to 100%.
A preferred NSAID is one that forms an oil upon melting, and preferably has a melting point of less than about 200xc2x0 C., more preferably less than about 160xc2x0 C., most preferably less than about 120xc2x0 C. The NSAID optionally contains at least one chiral carbon atom, in which event the NSAID present in the two phase liquid composition can be either a substantially pure stereoisomer of the chiral NSAID or a mixture of stereoisomers. Where one stereoisomer of a chiral NSAID has greater efficacy than another, a preferred composition contains the more effective stereoisomer in a relative proportion of at least about 60% of the NSAID, preferably at least about 70% of the NSAID, more preferably about 80% of the NSAID, most preferably about 90% of the NSAID. A composition in which at least 90% of the NSAID is in the form of the desired stereoisomer is considered to contain a xe2x80x9csubstantially pure stereoisomerxe2x80x9d of the chiral NSAID.
Examples of NSAIDs include ibuprofen, ketoprofen, flurbiprofen, fenoprofen, loxoprofen, suprofen, aluminoprofen, pranoprofen, piroxicam, pentazocine, aspirin, acetanilide, phenacetin, diclofenac, antipyrine, aminopyrine, phenyl salicylate, methyl salicylate, methenamine, carprofen, choline salicylate, salsalate, diflunisal, dihydroergotamine mesylate, ergotamine tartrate, indomethacin, meclofenamate, mefenamic acid, naproxen, oxyphenbutazone, phenylbutazone, sulindac and tolmetin. Ibuprofen, ketoprofen, flurbiprofen, pranoprofen, fenoprofen, naproxen, suprofen and aluminoprofen are examples of chiral NSAIDs. Preferred NSAIDs for use in a composition of the invention include ibuprofen, ketoprofen, flurbiprofen, fenoprofen and aspirin. A particularly preferred NSAID is the S-enantiomer of ibuprofen, S(+)-ibuprofen.
The first melting point depressing agent is an alcohol; preferably it is a monohydric alcohol. Preferred monohydric alcohols include isopropyl alcohol and ethyl alcohol; a preferred polyhydric alcohol is propylene glycol. One or more alcohols can be used in combination.
The water component of the composition can be pure water or an aqueous solution. An aqueous solution can be a buffer and/or can contain a solute, such as a salt.
In a preferred embodiment, the two phase liquid composition of the invention further contains at least one second melting point depressing agent, preferably in an amount of at least about {fraction (1/20)} of the weight of the NSAID, more preferably at least about {fraction (1/10)} of the weight of the NSAID; and preferably less than about xc2xe of the weight of the NSAID, more preferably less than about xc2xc of the weight of the NSAID. The second melting point depressing agent is preferably thymol, menthol, eucalyptol, eugenol, methyl salicylate, phenyl salicylate, capsaicin, butylated hydroxytoluene, a local anesthetic agent, an NSAID, or any combination thereof, except that in compositions containing as the active agent a substantially pure stereoisomer of a chiral NSAID, the second melting point depressing agent is not another, less active isomer of the chiral NSAID. Examples of local anesthetic agents include lidocaine, tetracaine, prilocaine, mepivacaine, etidocaine and benzocaine. The use of a second melting point depressing agent is preferred for NSAIDs having a melting point above about 50xc2x0 C. For example, a composition of the invention containing the NSAID S(+)-ibuprofen, which has a melting point of about 44xc2x0 C., can contain a first melting point depressing agent and water, in the appropriate amounts, to generate the oil phase, whereas compositions containing NSAIDs such as ketoprofen and flurbiprofen, which have melting points higher than 50xc2x0 C., preferably include a first melting point depressing agent and a second melting point depressing agent in order to generate the highest possible amount of the drug in the oil phase.
When the NSAID is a solid at ambient temperature, preferably a crystalline solid, melting of the NSAID yields an oil. The second melting point depressing agent can be a solid or an oil at ambient temperature. When the second melting point depressing agent is a solid, melting of the second melting point depressing agent yields an oil. Preferably, the NSAID and the second melting point depressing agent have melting points lower than about 200xc2x0 C.; more preferably, they have melting points lower than about 160xc2x0 C., most preferably lower than about 120xc2x0 C.
Methods for making the two phase liquid composition of the invention are also provided. Components of the composition are mixed together in amounts effective to form a two phase liquid composition consisting of an aqueous phase and an oil phase. Preferably, the aqueous and oil phases are homogeneous below about 37xc2x0 C., more preferably they are homogenous at or below about 25xc2x0 C. During mixing, the solid components) undergo a solid to liquid phase transition; that is, they melt. Simple mixing of the components at ambient temperature causes at least some melting of the solid components without heating. In some embodiments of the invention, an external source of heat is applied to the mixture to more quickly achieve a full xe2x80x9cmelt.xe2x80x9d When an external source of heat is used during the preparation of the composition, the mixture is preferably maintained at a temperature of less than about 50xc2x0 C.
The components of the two phase liquid composition of the invention partition between the aqueous phase and oil phase according to their individual physical and chemical properties to form an equilibrated system. For example, the NSAID can partition between the oil phase and the aqueous phase, in accordance with its relative solubility in each liquid phase.
Although the inventors do not intend to be bound by any particular theory or mechanism, it is believed that inclusion of the first and second melting point depressing agents in the mixture in accordance with the invention causes the solid component(s) to melt into the oil phase by depressing the melting point(s) of the solid component(s). More particularly, it is believed that inclusion of the first and second melting point depressing agents yields an oil phase having a higher concentration of NSAID, for example S(+)-ibuprofen, than has previously been achieved. Increasing the concentration of the NSAID in the oil phase is desirable because it enhances percutaneous absorption and efficacy. In compositions of the invention, the concentration of the NSAID in the oil phase can reach about 75% or higher, by weight, of the weight of the oil phase. This concentration has never been achieved by any previous methods. The remaining oil phase typically contains amounts of the melting point depressing agents and a trace amount of water.
The term xe2x80x9ctwo phase melt systemxe2x80x9d is used herein, particularly in the Examples, to describe a two phase liquid composition of the invention that has been generated by combining the components of the composition to effect an oily xe2x80x9cmelt statexe2x80x9d below about 37xc2x0 C., preferably at or below about 25xc2x0 C. It should be nonetheless understood that the composition of the invention is by no means limited to any particular method of making the composition. If no crystals remain in the oil phase and the aqueous phase of a resulting composition, it is considered that a complete melt has occurred; if crystals remain in the either the oil phase or the aqueous phase, only a partial melt has achieved. Compositions resulting from both complete or partial melts are included in the invention, although compositions resulting from complete melts are preferred.
The two phase liquid compositions of the invention are readily formulated into a cream, an emulsion, an ointment, a lotion, a lipophilic organogel, patch, or the like, that is effective in local delivery of the anti-inflammatory drug through the skin, and these pharmaceutical preparations or formulations are encompassed by the invention. A typical cream contains, by weight, at least about 0.1% NSAID, preferably at least about 0.5% NSAID, more preferably at least about 1% NSAID; and preferably less than about 30% NSAID, more preferably less than about 20% NSAID, most preferably less than about 10% NSAID. A preferred cream contains S(+)-ibuprofen as the anti-inflammatory drug, isopropyl alcohol or ethyl alcohol or both as the first melting point depressing agent, and thymol as the second melting point depressing agent. The pH of the formulation is preferably controlled such that the NSAID is supplied in a nonionized acidic form, which increases lipid solubility of the NSAID, making it more permeable through a lipid membrane.
The invention further provides a method for local transdermal delivery of an anti-inflammatory drug in animal, preferably a mammal, more preferably a human. The method employs topical application of the pharmaceutical formulation of the invention. The pharmaceutical formulation is expected to be safe and effective in delivering the anti-inflammatory drug through the skin of humans for clinical use and is suitable for use in veterinary or agricultural husbandry applications as well. The preparation can be administered to intact skin, wounded skin, or a mucus membrane of the animal. Optionally, the method includes covering the formulation with a dressing, such as a gauze, bandage, plaster, patch, or the like. The method can be performed whenever treatment of inflammation and/or pain is required or desired, such as in connection with local inflammatory and arthritic diseases such as rheumatoid arthritis, arthralgia, tendinitis, gout, and ankylosing spondylitis, and other related conditions. In a preferred embodiment, the NSAID has analgesic or antipyretic activities, or both, as well, and can be used to relieve pains associated with muscle ache, backache, neuralgia, dysmenorrhea, headache, sunburn and fever. The method preferably utilizes a pharmaceutical formulation comprising S(+)-ibuprofen due to its potent anti-inflammatory, analgesic, and antipyretic activities.